Periodontitis is twice as prevalent in diabetics as in non-diabetics. Diabetic periodontal diseases are more severe and refractory because T2DM and obesity trigger the release of excess inflammatory factors, such as TNF-1 and IL-6, which in turn stimulate osteoclasts to resorb the alveolar bone that supports the teeth. Adiponectin, a fat cell derived hormone, is emerging as a potent molecule with multiple biological functions including regulating insulin sensitivity, suppressing inflammation, and improving diabetic symptoms. It also promotes osteoblastic differentiation and bone formation. Our recent studies have shown that adiponectin inhibits osteoclast differentiation and increases osteoclast apoptosis. Our long-term objective is to identify and characterize an ideal endogenous mediator as a potent therapeutic remedy for the treatment of the widely prevalent T2DM-associated periodontitis. The objective of this application is to investigate the mechanisms of adiponectin in the pathogenesis of T2DM-associated periodontitis and to specifically reconstruct the inflammatorily damaged periodontal tissues by the replenishment of adiponectin in vivo. The central hypothesis to be tested is that the decreased level of adiponectin, together with the consequent removal of its suppressive effects on osteoclasts and proinflammatory factors, contributes to the pathogenesis of T2DM and T2DM-associated periodontitis. Also, a systemic adiponectin infusion promotes the reconstruction of the damaged periodontal tissues. Aim 1: Using an animal model for the first time to determine the effects of anti-inflammatory factor in periodontal pathogenesis including inhibition of differentiation of osteoclasts that directly resorb alveolar bone. Aim 2: To determine the therapeutic effect of systemic adiponectin infusion in dampening inflammation and in reconstruction of damaged periodontal tissues in vivo. Combining our experience and the expert assistance from Drs. Salomon Amar at Boston University and Gerard Karsenty at Columbia University, the completion of this novel project will definitely provide an advanced bioengineering-based tool to allow precise and predictable control of inflammatory resolution and reconstruction of damaged periodontal tissues. PUBLIC HEALTH RELEVANCE: Prevalent type II diabetes mellitus and obesity predispose patients to refractory periodontitis leading to tooth loss, and the inflammatory factors released from periodontal foci enhance and accelerate the formers. Adiponectin, a fat tissue derived hormone, will prove to be a potent bona fide therapeutic molecule, for the first time, to break the "vicious cycle" and to provide a novel, unique and efficient remedy for treating this devastating and sometimes rampant disease.